Policitemia vera: resistencia/intolerancia

a hidroxiurea

Madrid, 6 junio 2019

Alberto Alvarez Larrán

Servicio de Hematología, Hospital Clínic, Barcelona

Meet the Expert, GEMFIN

Caso clínico

Mujer de 34 años, fumadora, ingresada en Hepatología para

estudio y tratamiento de síndrome de Budd-Chiari. Al

diagnóstico presentaba:

• Hb 16.6 g/dL, Hto 0.52 L/L, leucocitos 12x109/L, plaquetas

594x109/L

• Eritropoyetina sérica normal

• Masa eritrocitaria aumentada

• JAK2V617F mutado

• Crecimiento endógeno de colonias eritroides

Se inició tratamiento anticoagulante, se colocó un TIPS y tras

establecerse el diagnóstico de policitemia vera se remitió a

Hemoterapia para la realización de flebotomías periódicas con

el objetivo de mantener el Hto < 45%

30

35

40

45

50

55

60

IFN Hidroxiurea

Anticoagulación

Retrombosis

Retrombosis Retrombosis

IFN Hidroxiurea

1 2 3 4 5 6 7

Años tras el diagnóstico

Hem

ato

crito

, %

Embarazo

AAS

Flebotomías

Caso clínico

Durante el último año se mantuvo con hidroxiurea 1000 mg/día

ya que no toleraba el incremento de dosis por aparición de

sintomatología digestiva.

Se remitió de nuevo a Hemoterapia donde se realizaron 3

flebotomías en 1 mes. La última analítica mostraba:

Hematies 5.76 x1012/L, Hb 125 g/L, Hto 43L/L, VCM 78fL,

leucocitos 10.1 x109/L, plaquetas 396 x109/L.

¿Cumple los criterios de resistencia/intolerancia

a la hidroxiurea definidos por la ELN?

Resistencia/Intolerancia a HU

Barosi et al, BJH 2010

Citopenias

Esplenomegalia masiva

Necesidad de flebotomías

Mieloproliferación

incontrolada

Toxicidad extra-

hematológica

2 g/día > 3 meses

A la mínima dosis

para mantener la

respuesta

A cualquier dosis

Frequency of resistance/intolerance to hydroxyurea in 890 patients with PV

Patients

(%

)

Alvarez-Larrán et al, BJH

Resistance / Intolerance n=137 (15,4%)

3,3 1,6 0,8

1,7

9

0

5

10

15

20

25

30

Phlebotomies Myeloproliferation Splenomegaly Cytopenia Extrahematological toxicity

Median follow up: 4.6 years

Extra-hematological toxicity: Spanish Registry of PV (n=890)

6

3

0,1 0

5

10

15

20

25

30

Leg ulcers Mucocutaneous Fever

Unacceptable toxicity n=79 (9%)

4,4

1,6 0,1 0,1 0,7

0

5

10

15

20

25

30

Manageable toxicity n= 62 (7%)

Patients

, %

Patients

(%

)

Alvarez-Larrán et al, BJH 2016

Resistance/Intolerance to HU: modified criteria

McMullin et al, BJH 2015

Cytopenia

Massive splenomegaly

Need of phlebotomies

Uncontrolled

myeloproliferation

Extrahematological toxicity

After 3 months at

MTD of HU

At the lowest dose

of HU to achieve

response

At any HU dose

Disease-related thrombosis

or bleeding

Disease-related symptoms At any HU dose

New

New

New

Resistance/Intolerance to HU: modified criteria

McMullin et al, BJH 2015

Cytopenia

Massive splenomegaly

Need of phlebotomies

Uncontrolled

myeloproliferation

Extrahematological toxicity

After 3 months at

MTD of HU

At the lowest dose

of HU to achieve

response

At any HU dose

Disease-related thrombosis

or bleeding

Disease-related symptoms At any HU dose

Case 1!!!

Case 1!!!

Case 1!!!

Clinical characteristics of patients requiring frequent phlebotomies*

• Younger age (65 vs 70 years, p=0.02)

• Higher Htc before HU start (55% vs 51%, p<0.0001)

• Similar frequency of cardiovascular risk factors and history of thrombosis,

• No differences regarding leukocyte and platelet counts

• Similar JAK2V617F allele burden

• Higher doses of HU

• Higher frequency of intolerance to HU

Inadequate dose of HU according to disease proliferation

*In comparison with those not requiring frequent phlebotomies

Alvarez-Larrán et al, Haematologica 2017

Hematocrit control according to need of phlebotomies under HU therapy

55

48 46,5 47

48 47

51

48

35

40

45

50

55

60

Pre-HU 6 12 18 24 36 48 60

> 3 phlebotomies/year n= 85 (16%)

< 3 phlebotomies/year n= 448 (84%)

Month of HU therapy

Alvarez-Larrán et al, Haematologica 2017

0

<3 phlebotomies/year

≥3 phlebotomies/year

P < .0001

Th

ro

mb

os

is,

%

0

20

40

60

80

100

12 24 36

Months of Therapy

48 60

P < .0001

Alvarez-Larrán et al, Haematologica 2017

Multivariate analysis of risk factors predicting thrombosis in 533 patients treated with HU

Clinical feature HR (95%CI) P value

Male sex 0.5 (0.25-1.1) 0.08

Thrombosis at PV diagnosis 4.7 (2.3-9.8) <0.0001

Cardiovascular risk factors 2.2 (0.8-5.6) 0.1

Three or more PHL per year 3.3 (1.5-6.9) 0.002

Clinical meaning of phlebotomies under HU

Case 2

Phlebotomies

Antiplatelet therapy

Hydroxyurea

2003 2016

• Progressive

splenomegaly

• Night sweats

• Massive spleen

• Hb 174 g/L, Leukocytes

30x109/L, platelets 281x109/L

• Leukoeryhthroblastic picture

• JAK2V617F: 93%

• Bone marrow: intermediate

between PV and MF

2018

• Male

• 43 years

• Ischemic stroke

Ruxolitinib

Myelofibrotic transformation

0

Any criteria of HU intolerance/resistance

No HU intolerance/resistance

Tra

ns

form

ati

on

, %

0

20

40

60

80

100

5 10 15

Years

20 25 30 0

Development of cytopenia

No development of cytopenia

Tra

ns

form

ati

on

, %

0

20

40

60

80

100

5 10 15

Years

Myelofibrosis Acute Myeloid Leukemia

20 25 30

p= 0,026

Alvarez-Larran et al., Br J Haematol. 2016 Mar;172(5):786-93

Myelofibrosis

HR (95%CI) P

Need for phlebotomies 1.2(0.2-9.2) 0.8

Uncontrolled myeloproliferation

0.2(0.02-2.2) 0.2

Splenomegaly* 9.1(2.3-35.9) 0.002

Cytopenia 5.1(1.9-13.7) 0.001

Extrahematological toxicity 1.6(0.7-3.6) 0.2

* Failure to reduce massive splenomegaly (>10 cm from the costal margin) by >50% by palpation OR resolve splenomegaly-related symptoms HR: hazard ratio.

Clinical meaning of resistance/intolerance to HU

0

100

200

300

400

30

35

40

45

50

55

Pla

tele

ts x

10

9/L

H

em

ato

cri

t, %

Phlebotomies

Hu dose

Myelofibrosis

Case 3: 65 years-old male with JAK2V617F-positive

PV presenting with pulmonary embolism

1 y 2 y

Oral anticoagulation

Progression to acute leukemia

0

Any criteria of HU intolerance/resistance

No HU intolerance/resistance

Tran

sfo

rm

ati

on

, %

0

20

40

60

80

100

5 10 15

Years

20 25 30 0

Development of cytopenia

No development of cytopenia

Tran

sfo

rm

ati

on

, %

0

20

40

60

80

100

5 10 15

Years

Myelofibrosis Acute Myeloid Leukemia

20 25 30

HR: 20,3 (95%CI: 5.4-76.5) p=0,001*

* Corrected for age, leukocytosis at diagnosis and

sequential treatment with busulphan, P32,

pipobroman or melphalan Alvarez-Larran et al., Br J Haematol. 2016 Mar;172(5):786-93

Senín et al, Annals Hematol 2018

Patients developing cytopenia

under HU have a high genomic

instability as demonstrated by a

higher frequency of mutations in

DNMT3A, SRSF2, TP53,

RUNX1 enes

Clinical meaning of cytopenia under HU

Probability of progression to myelodysplstic

syndrome/acute myeloid leukemia in patients with

resistance/intolerance to HU

Patients with TP53 disruption/aneuploidy or with chromatine/spliceosome mutations

Patients belonging to other genomic subgroups

p <0.0001

Díaz et al, EHA 2019

Second line therapy in PV: ELN 2018 recommendations

Barbui T, et al. Leukemia 2018

• Ruxolitinib

• Interferon in young patients

• Hydroxyurea if not previously used

• Busulfan in the elderly

Ruxolitinib in PV: Response study

Primary composite endpoint: hematocrit control in the absence of phlebotomy

and ≥35% reduction in spleen volume at Week 32

Secondary endpoints: Complete hematologic remission at Week 32; % of

subjects who maintain primary endpoint response for ≥48 weeks

BAT: hydroxyurea, IFN/peg-IFN, anagrelide, pipobroman, IMIDS or observation

Kiladjian et al, EHA 2015

n = 91 (83%)

n = 98

n = 0

Ruxolitinib n=110

Vannucchi et al, NEJM 2015

Starting dose: 10 mg/ 12h

Treatment modalities in Response Trial

59% 12%

15%

Response: primary objective week 32

20,9

38,2

60,0

0,9 0,9

19,6

0

10

20

30

40

50

60

70

Composite Primary End Point

> 35% Reduction in Spleen Volume

Hematocrit Control

Ruxolitinib Standard Therapy

Vannucchi et al NEJM 2015

P < 0.001

Durability of primary response week 208

Kiladjian et al, ASH 2017, abstract 322

• 6 of 25 primary responders have progressed.

• K-M estimates of duration of hematocrit control: 73%

• K-M estimates of duration of spleen response: 86%

100

80

60

40

20

0

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 6 18 30 42 54 66 78 90 102 114 126 138 150 162 174 186 198 210 222

0 0 0 0 0 0 1 2 2 2 2 2 2 2 3 3 3 4 4 4 4 4 4 4 4 4 4 5 5 5 5 5 6 6 6 6 6 6 6

8 8 7 0 22 22 22 21 21 21 20 20 20 20 19 19 19 18 18 18 17 17 17 14 14 13 12 12 25 25 25 25 25 25 24 22 22 22 22

No. of responders/events/censor: 25/6/19

Kaplan-Meier median: Not reached

Duration of response (Weeks)

Pro

bab

ilit

y (

%)

Events

At Risk

Censoring times

Ruxolitinib

+

Durability of Hct control with ruxolitinib

Verstovsek et al, Haematologica 2016

24

49

9

5

0

10

20

30

40

50

60

CHR MPN-SAF

Ruxolitinib BAT

Patients

,%

Efficacy of ruxolitinib in polycythemia vera: RESPONSE TRIAL

• CHR: Hematocrit control, platelets < 400x109/L and WBC < 10x109

• MPN-SAF: percentage of patients with > 50% improvement in MPN-SAF symptom score

Vannucchi et al NEJM 2015

RESPONSE: Adverse Events of Interest

Ruxo BAT-CO

Rate* Rate*

Thrombotic events 1.2 2.9

Nonmelanoma skin cancer 6.6 2.5

Herpes-Zoster 4.9 4.2

Myelofibrosis 2.2 1.9

AML 0.2 0.3

Kiladjian et al, ASH 2017, abstract 322,

* eventsx100 person-years (Follow-up: 409 and 310 patient-years for Ruxo and BAT-CO,

respectively)

RESPONSE-2 Study Design

• Ruxolitinib-randomized patients had their doses individually titrated for efficacy and safety (to a maximum of 25 mg bid)

• Investigator-selected BAT as monotherapy included HU (at a tolerated dose if the patient were likely to receive benefit), interferon (IFN)/peg-IFN, anagrelide, pipobroman, immunomodulatory drugs, or no medication

• All patients received low-dose aspirin unless medically contraindicated

• Data cutoff date: 29 September 2015

BAT

Week 28 (primary analysis)

Week 80

n = 74

n = 75

Crossover to ruxolitinib

• Resistance to or intolerance of HU (modified ELN criteria)

• Phlebotomy requirement

• Nonpalpable spleen

• ECOG PS ≤ 2

Prerandomization (day −35)

Hct, 40%-45%

Ra

nd

om

ize

d (

1:1

)

Extended treatment

phase Ruxolitinib 10 mg bid

Week 260

Week 260

Final analysis

bid, twice daily; ECOG, Eastern Cooperative Oncology Group; ELN, European LeukemiaNet; PS, performance status. 26

Response-2: ruxolitinib in resistant/intolerant patients without splenomegaly

Endpoint Ruxolitinib BAT

Hct control 62%

(P < .0001) 19%

CHR 23%

(P = .0019) 5%

≥50% improvement in MPN-SAF TSS 45% 23%

Griesshammer et al, EHA 2017

Eficacia de ruxolitinib en la práctica clínica real: análisis de 68 pacientes

procedentes del Registro Español de Policitemia Vera (SEHH2019)

Basal 6 meses 12 meses

Prurito 57% 31% 6%

S. microvascular 36% 8% 0%

S. constitucional 15% 15% 12%

Esplenomegalia palpable 35% 16% 6%

Hematocrito > 45% 53% 42% 29%

Leucocitos > 10x109/L 51% 46% 47%

Plaquetas > 400x109/L 58% 58% 53%

Leucocitosis y

trombocitosis

37% 31% 23%

Respuesta hematológica

completa

18% 21% 18%

Busulfan

• Second-line: patients resistant/intolerant to HU (> 65 years)

• Schedule: 2 mg/day. Close monitoring and stop when normalization of

blood counts

• CHR 83%. Median time to response 203 days.

• Median duration of response: 45 months

• Rate of thrombosis: 5.1 events x 100 person-years

• Hematological toxicity 22%

• Acute myeloid leukemia in JAK2V617F-negative clone carrying aditional

mutations

EORTC, BJC 1981

Messinezy et al, BJH 1985

Alvarez-Larrán et al, Anals of Hematol 2014

Evolución clonal en paciente tratado con Busulfán

JAK2V617F DNMT3A

ASXL1

SETBP1

Dx 2005

STOP por PRURITO

STOP por PANCITOPENIA

Flebotomías AAS

RHC Hb 7,9 NF 0,75 Plq 47

Hb 12,7 Leuc 12 Plq 277

HU BUSULFÁN AAS

2005 2008 2011 2012 2015 2018

PV

Cortesía Dra A. Senín

Selección del paciente candidato a busulfán en segunda línea

• Edad > 70 años

• Toxicidad extra-hematológica por hidroxiurea

• Buena disposición para realizar controles

frecuentes

• Adecuada adherencia al tratamiento

• Tratamiento combinado si trombocitosis extrema

(anagrelide)

Resistencia a Hidroxiurea

Ruxolitinib Ensayo clínico

Ruxolitinib Busulfán Interferón

1. Descartar transformación de la enfermedad

2. Adecuar el tratamiento al perfil del paciente: edad,

comorbilidades y tipo de resistencia/intolerancia

Sintomatología

constitucional

Esplenomegalia

Citopenias

Toxicidad extra-

hematológica

Altas dosis de Hu

para control Hto Trombocitosis

aislada

Anagrelide Ruxolitinib Interferón

Conclusiones

• Los pacientes con resistencia/intolerancia a la hidroxiurea se

caracterizan por una mayor complejidad molecular especialmente

aquellos que desarrollan citopenias

• La necesidad de flebotomías frecuentes traduce un mal control del

hematocrito y mayor riesgo de trombosis

• La elección del tratamiento de segunda línea tiene que adaptarse

a las características del paciente

• El interferón podría ser una opción para pacientes jóvenes

• El busulfán requiere experiencia en el manejo y una adecuada

selección del paciente

• Ruxolitinib constituye una nueva alternativa para pacientes con

respuesta inadecuada o intolerancia a hidroxiurea con un

adecuado perfil de eficacia y seguridad

GEMFIN: MPN Spanish Group

Muchas gracias!!!